α+-thalassemia protects African children from severe malaria

Abstract

The high frequency of ␣ ؉ -thalassemia in malaria-endemic regions may reflect natural selection due to protection from potentially fatal severe malaria. In Africa, bearing 90% of global malaria morbidity and mortality, this has not yet been observed. We tested this hypothesis in an unmatched case-control study among 301 Ghanaian children with severe malaria and 2107 controls (62% parasitemic). In control children, ␣ ؉ -thalassemia affected neither prevalence nor density of Plasmodium falciparum. However, heterozygous ␣ ؉ -thalassemia was observed in 32.6% of controls but in only 26.2% of cases (odds ratio [ IntroductionSevere Plasmodium falciparum malaria is a major cause of death in sub-Saharan Africa, particularly in children younger than 5 years of age. 1 Interindividual variation in susceptibility and manifestation can be attributed partially to innate host factors such as the sickle cell trait. [2][3][4] According to Haldane's "malaria hypothesis," 5 these factors are subject to selection in endemic regions because of the resistance they confer against malaria. Another hemoglobin disorder, ␣ ϩ -thalassemia, reaches a prevalence of more than 80% in parts of Southeast Asia and Melanesia. [6][7][8] Heterozygosity is characterized by the commonly deletional loss of one of the duplicated ␣-globin genes (Ϫ␣/␣␣) and slight hematologic changes. Homozygous individuals (Ϫ␣/Ϫ␣) have mild microcytic anemia. 9 In Melanesia, the geographic correlation between the prevalence of ␣ ϩ -thalassemia and malarial endemicity suggests natural selection. 6 In one case-control study in Papua New Guinea, the risk of severe malaria was reduced by 60% and 34% in homozygous and heterozygous children, respectively. 7 In sub-Saharan Africa, ␣ ϩ -thalassemia affects up to 50% of the population, but protection against uncomplicated or severe malaria could not be demonstrated so far. 3,9,10 We examined whether ␣ ϩ -thalassemia confers protection from severe falciparum malaria in Ghana. Study design Patients and controlsWe conducted an unmatched case-control study in the city of Tamale and its vicinity, northern Ghana, during the rainy season 2002 (August to November). In the study area, malaria is hyperendemic (F.P.M., unpublished observations, December 1, 2003). Ethical clearance was obtained from the Ethics Committee, University for Development Studies, Tamale, and informed consent, from the participants' parents. We recruited 290 children with severe malaria according to WHO definition at Tamale Teaching Hospital. 1,11 An additional 11 children with severe malaria were detected during the survey mentioned later in this paragraph and classified as cases. In the 301 index patients, symptoms defining severe malaria were as follows: severe anemia, 57%; prostration, 32%; respiratory distress, 22%; multiple convulsions, 20%; impaired consciousness, 19%; jaundice, 11%; circulatory collapse, 3%; and hemoglobinuria, 3%. Controls were 2107 children from Tamale and the surrounding districts who were recruited following a 2-stage cluster sampling st...

An investigation of the protective effect of alpha+‐thalassaemia against severe Plasmodium falciparum amongst children in Kumasi, Ghana

“…The reasons for the lack of protective effect against Plasmodium falciparum in the homozygous alpha + -thalassaemia were due to its low proportion and the associated statistical limitations (Mockenhaupt et al, 2004a). Subsequent studies in Kenya clearly conflicted with the Ghanaian report but agreed with the findings from Papua New Guinea (Williams et al, 2005b).…”

“…The -α 3.7 kb deletion alpha + -thalassaemias, which are predominant in Africa, have been suggested to confer protection from severe Plasmodium falciparum malaria and both the homozygous and heterozygous alpha + -thalassaemia has been implicated (Mockenhaupt et al, 2004a).…”

Population genetics of malaria resistance in humans

“…In addition, several studies have shown protection from severe malaria for individuals with a þ thalassemia, compared with individuals without thalassemia (Allen et al, 1997;Mockenhaupt et al, 2004;Williams et al, 2005b). In a large case-control study in Kenya (Williams et al, 2005b), the OR values, standardized to the normal aa/aa genotype, for a þ heterozygotes and homozygotes in Kenya are 0.623 and 0.522 for severe malaria, respectively (Hedrick, 2011b).…”

Selection and Mutation for α Thalassemia in Nonmalarial and Malarial Environments

“…Another study in Ghana (Mockenhaupt et al, 2004) also found a large effect with a standardized OR value for α + thalassemia heterozygotes of 0.577. However, they did not observe an effect in homozygotes, a finding that Williams et al (2005a) suggested was due to low statistical power.…”